1. Field of the Invention
The present invention relates to a composition for detecting beta amyloid aggregates and a composition for diagnosing beta amyloid aggregation disease, comprising 2-styrilpyridizine-3(2H)-one derivatives or its pharmaceutically acceptable salt, and a fluorescence reagent for detecting beta amyloid aggregates comprising the composition for detecting beta amyloid aggregates, and a diagnostic kit for diagnosing beta amyloid aggregation disease comprising the composition for diagnosing beta amyloid aggregation disease.
Also, the present invention relates to a method for detecting beta amyloid aggregates, comprising using 2-styrilpyridizine-3(2H)-one derivatives or its pharmaceutically acceptable salt to provide information for beta amyloid aggregation disease diagnosis.
2. Background of the Invention
Data of the Ministry of Health and Society show that the number of dementia patients was nearly 280,000 in 1998, and raised to 400,000 in 2002, domestically. According to Alzheimer's disease association data in the United States, four million people suffer from Alzheimer and it is estimated that the number may reach fourteen million people in 2050. It is estimated that twenty-two million people will be troubled with Alzheimer worldwide in 2005.
The main reason for the sharp increase in the number of dementia patients throughout the world is aging in society. As an average life is increased, aging population has been increased to naturally increase the number of dementia patients. Korea, which has achieved the rapid economic growth, is quickly transforming into an aging society, and thus, an attack rate of senile dementia, stroke, Parkinson's disease represented by Alzheimer's disease is on the rise. Improved data of the United Nations Food and Agriculture Organization (FAO) estimate that a population growth of an age group older than 60 is global trends, and even in Asia, senior citizens over sixty is anticipated to be jumped from 8% of the general population in 2000 to 25% as of 2050. The graying and the attack rate of dementia are very closely related. In Korea, 15% of aging population by age 75 to 79 suffers from dementia, and 39% of aging population over age 80 is dementia patents. Also, a dementia prevalence rate of women is higher than men, but the precise cause is unknown and the medical world in many countries has sought to find the cause competitively.
Alzheimer's disease is a progressive neurodegenerative disease featuring a reduction in cognitive ability, irreversible memory loss, a loss of sense of direction, and language capabilities impairment as nerve cells of the brain are reduced Alzheimer's patients have a plurality of senile plaques comprised of numerous neurofibrillary tangles (NFT) formed by beta amyloid (Aβ) peptide, and hyperphophorylated-tau protein fiber in the brain (Ginsberg, S. D., et al., “Molecular Pathology of Alzheimer's Disease and Related Disorders,” in Cerebral Cortex: Neurodegenerative and Age-related Changes in Structure and Function of Cerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp. 603-654; Vogelsberg-Ragaglia, V., et al., “Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease,” Alzheimer's Disease, Lippincot, Williams & Wilkins, Philadelphia, Pa. (1999), pp. 359-372). Whether beta amyloid is a direct cause or a result of a cause of Alzheimer's disease is still uncertain, but so far, aggregates based on accumulation of beta amyloid has been the most typical syndrome or hallmark of Alzheimer's disease. Thus, ADNI (Alzheimer's Disease Neuroimaging Initiative) organized by NIA (National Institute of Aging) in the US in 2004 labeled beta amyloid aggregates as the most powerful biomarker of Alzheimer's disease, and thus, quantizing accumulation of aggregates of beta amyloid by using a noninvasive biomolecular image may make breakthrough in an early eiagnosis and treatment of Alzheimer's disease, and the process of Alzheimer's disease may be suppressed by injecting drug suppressing formation of beta amyloid aggregates and tangles.
Compounds having fluorescence that may be easily bound to beta amyloid aggregates to readily indicate the presence have been actively researched in order to diagnose diseases that may be diagnosed by quantitatively detecting beta amyloid aggregates including Alzheimer's disease. A typical one of such compounds is congo red (CR), and Alzheimer's disease may be definitely diagnosed by conducting a postmortem and staining the brain with congo red. However, this method cannot be used for a living person. The reason is because congo red is strongly water-soluble, which is, thus, cannot pass through brain blood barrier (BBB), so, although it is injected to a living person, it cannot enter the brain. Thus, a marker that may be bound to beta amyloid aggregates and tangles and able to pass through BBB may be injected into a human body and a distribution thereof in the brain may be imaged to thereby diagnose a disease pathologically featuring accumulation of beta amyloid aggregates such as Alzheimer's disease, or the like,
Besides congo red, one of the first developed compounds is derivatives of Chrysamine-G, but it is also too low a level to pass through the BBB, making it impossible to be used in actuality. (Klunk W E, Debnath M L, Pettegrew J W. Development of small molecule probes for the beta amyloid protein of Alzheimer's disease. Neurobiol Aging 1994; 15:691-8. Klunk W E, Debnath M L, Pettegrew J W. Chrysamine-G binding to Alzheimer and control brain: Autopsy study of a new amyloid probe. Neurobiol Aging 1995; 16:541-8.)
Afterwards, as 6-dialkylamino-2-naphthylethylidene (FDDNP) derivatives and thioflavin-T (ThT)-based derivatives were developed, research was activated. (Agdeppa E D, Kepe V, Liu J, Flores-Tones S, Satyamurthy N, Petric A, Cole G M, Small G W, Huang S C, Barrio J R. Binding properties of radiofluorinated 6-dialkylamino-2-naphthylethylidene derivatives as positron emission tomography imaging probes for β-amyloid plaques in Alzheimer's disease. J Neuroscience 2001; 21:1-5. Mathis C A, Bacskai B J, Kajdasz S T, MlLellan M E, Frosch M P, Hyman B T, Holt D P, Wang Y, Huang G-F, Debnath M L, Klunk W E. A lipophilic thioflavin-T derivative for positron emission tomography (PET) imaging of amyloid in brain. Bioorg Med Chem Lett 2002; 12:295-298.)
Also, various benzothiazole derivatives and stilbene derivatives were filed for patent as radioactive isotope labeled compounds that may be able to image beta amyloid. (US Patent Pub. No. 2002/0133019 A1, W. E. Klunk, C. A. Mathis Jr, Thioflavin derivatives for use in antemortem diagnosis of Alzheimer's disease and vivo imaging and prevention of amyloid deposition; US Patent Pub. No. 2003/0149250 A1, H. F. Kung, M-P. Kung, Z-P. Zhuang, Stilbene derivatives and their use for binding and imaging amyloid plaques).
However, the currently developed beta amyloid detecting fluorescence legand has a complicate preparation process, a large molecular mass, and does not show a great change in fluorescence properties when it is bound with beta amyloid aggregates. Also, it is bound also with phosphorylated tau protein fiber, rather than selectively only with beta amyloid, so it does not have high detection selectivity. Also, the beta amyloid detecting fluorescence legand has a low uptake rate in an animal testing, and it is not easy to remove legand from the brain, having a difficulty in using it in actuality.
Due to the problems of the conventional beta amyloid detecting legands, demand for the development of a specific reagent in terms of diagnosis reagent for staining beta amyloid aggregates that may be able to overcome the problems has continued.